7 Project Summary/Abstract Several prior studies have assessed whether individual prescription medications are associated with weight gain and increased risk for conditions such as diabetes and high cholesterol. These negative health effects from medications are a particular concern for medications used to treat chronic disease, which often require very long term or lifelong treatment. Patients also identify weight gain as a common reason for medication nonadherence, leading to worse health outcomes. Limitations of prior studies include limited long-term follow- up, lack of comparison of all subclasses or commonly-prescribed individual medications within a class, and lack of use of causal methodologies that can help manage baseline and time-varying differences in patients prescribed different medications. Prior studies have typically not been large enough to determine whether associations differ by age when medications are initiated or by other patient characteristics, such as race, gender, and weight status. Using data on patients in a large network of healthcare institutions, this study will be a comprehensive assessment of weight gain and metabolic risk up to 10.5 years after initiating medications used to treat diabetes, high blood pressure, epilepsy, depression, psychoses, as well as contraceptives. These are all classes used to treat chronic diseases and have been associated with weight gain and metabolic risk; each of these classes also have several choices that can be used for treatment. The study will include children and adults and will involve separate evaluations of the 6 medication classes, comparing effects between subclasses and commonly-prescribed individual medications within each class. The setting for the study will be 19 diverse healthcare institutions participating in the National Patient-Centered Clinical Research Network (PCORnet). PCORnet facilitates cross-institutional, comparative effectiveness studies though use of a Common Data Model, in which each institution organizes its clinical information in the same format allowing for straightforward merging of data across sites. The first study Aim will be a detailed data quality assessment that will measure deviations from expected patterns of weight and height and rates of medication prescriptions in each class. This Aim will adapt existing data quality methods to allow for troubleshooting and remediating data issues and will produce an approach that can be scaled across PCORnet and other healthcare networks. The second Aim will be an examination of medication initiation and weight outcomes, incident diabetes, and change in cholesterol, and the third Aim will assess more sustained use of medications. In these latter Aims, we will incorporate advanced statistical methods that can account for differences in patients in novel ways, both at baseline and over the course of follow-up. This large-scale study will be the most comprehensive study to date of medication-induced weight gain and metabolic risk and will provide important, actionable information to help patients and clinicians make the most informed choices about medications.